Cis-regulatory elements (CREs) drive tissue- and cell-specific gene expression and are essential for safe, sustainable genetic control strategies in pest and vector insects, including the engineering of gene drives in the primary human-malaria vector Anopheles gambiae. Yet CREs remain poorly defined in mosquitoes due to limited computational tools and practical methods for identification and validation. We present a systematic in silico approach for CRE discovery, correlating targeted DNA-motif searches with gene expression, followed by frequency and distribution analysis within putative promoter regions. Applied to the A. gambiae germline, this approach identified hundreds of putative CREs significantly correlated with germline expression in one or both sexes, often linked to distinct sperm developmental stages and chromosomal locations, suggesting roles in broader regulatory mechanisms such as dosage compensation and meiotic silencing. When mapped onto pre-characterised germline promoters, CRE distribution aligned with regions associated with experimental expression patterns. Finally, we validated a top-ranked testis-enriched CRE using an in vivo dual-reporter assay, showing that mutation of conserved nucleotides drastically altered male germline expression. To the best of our knowledge this work provides the first nucleotide-resolution regulatory genome annotation of the A. gambiae germline, offering a transferable framework to aid promoter design for genetic control strategies against malaria mosquitoes and other insect pests.
Visual impairment affects over 2.2 billion people worldwide and the major causes include age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. For research in these areas, although animal models offer a more physiologically complex system than in vitro approaches, their use raises ethical considerations, and species-specific differences such as variations in protein sequences and signaling pathways. This can limit the direct translatability of the outcomes. Traditional 2-D cell cultures, in contrast, lack the multicellular organization and dynamic microenvironment necessary to replicate human retinal complexity. Retinal organoids (ROs), three-dimensional tissue constructs derived from pluripotent stem cells, have emerged as a promising model due to their human origin and complex cellular interactions that cannot be achieved in conventional 2-D/3-D co-culture models. In this review, we provide a brief overview of the evolution from 2-D to 3-D retinal models, highlight the structural and functional features of ROs including the presence of layered retinal architecture, photoreceptor outer segment formation, and light-responsive electrophysiological activity and summarize their applications in disease modeling, drug discovery, and gene and cell therapy. ROs represent a significant advancement over traditional models by enabling the recapitulation of human-specific retinal development, facilitating the study of patient-derived disease phenotypes, and providing a platform for personalized therapeutic screening. Their development has deepened understanding of pathological mechanisms in conditions such as retinitis pigmentosa and AMD, while enabling preclinical testing of targeted interventions like CRISPR-based gene editing and photoreceptor cell replacement. Nonetheless, challenges remain in fully replicating retinal vascularization, long-term functional maturation, and synaptic connectivity, underscoring the need for continued refinement and integration with complementary model systems.
Human biomonitoring (HBM) is crucial for evaluating exposure to diet-related contaminants, whose effects may pose substantial health risks. Saliva is recognized as a promising non-invasive biological matrix due to its ease of collection and potential to reflect external and systemic exposure. However, suitability for monitoring dietary hazardous compounds remains uncertain. To assess the potential of saliva as a biomonitoring matrix for diet-related contaminants, identify compounds with robust diet-related associations, and highlight knowledge gaps. A systematic literature review was conducted to screen over 500 diet-related contaminants analyzed in saliva. Detailed information was extracted only for contaminants quantitatively measured in saliva, including concentration ranges, sample sizes, and analytical methods. Evidence of correlations with systemic concentrations, exposure pathways, and individual or lifestyle factors was compiled into a FAIR database to provide an integrated evaluation of saliva's biomonitoring potential. Only a limited subset of contaminant groups, including nitrite/nitrate, heavy metals, bisphenols, polycyclic aromatic hydrocarbons (PAHs), biogenic amines, pesticides, advanced glycation end products (AGEs), perchlorate, microplastics (MPs), parabens and phthalates, have been quantitatively measured in saliva. Compounds such as nitrate, arsenic, AGEs, pesticides and perchlorate demonstrate moderate to strong correlations between salivary and systemic levels, supporting saliva's potential to estimate exposure. Conversely, substances like PAHs, MPs, phthalates and parabens generally show weak or no correlation, reflecting recent or localised exposures rather than cumulative burden. Salivary composition is influenced by intrinsic and extrinsic factors, including diet, oral microbiota, physiology, and sampling conditions, resulting in high interindividual variability. Despite challenges, low salivary concentrations and lack of standardized collection protocols, saliva offers advantages for biomonitoring vulnerable populations, such as children and pregnant women. Harmonized collection procedures, validated sensitive methods, predictive models accounting for variability and exposure context, could establish saliva as a reliable complementary or alternative matrix for assessing human exposure to dietary and environmental contaminants. This systematic review synthesizes findings from 104 studies, covering over 500 diet-related contaminants measured in saliva, and compiles them into a FAIR database, providing the most comprehensive resource to date for saliva-based biomonitoring. Compounds such as nitrate, arsenic, advanced glycation end-products (AGEs), pesticides, and perchlorate show meaningful correlations with systemic levels, supporting saliva's potential as a non-invasive matrix for assessing human exposure. To fully realize saliva's potential, standardized collection protocols, validated analytical methods, and predictive models that account for interindividual variability and exposure context are urgently needed, enabling more accurate and ethical monitoring of vulnerable populations.
In this review we comprehensively discuss organic cation transporter novel 1 (OCTN1), encoded by the SLC22A4 gene as a member in the solute carrier 22 (SLC22) family, which facilitates the cellular transport of diverse cationic and zwitterionic substrates. OCTN1 is highly expressed in many vital organs in humans, where it facilitates absorption and distribution of both endogenous compounds and therapeutic drugs. Among its substrates, ergothioneine (EGT) serves as the primary antioxidant and anti-inflammatory molecule, underscoring the essential role of OCTN1 in cellular defense and inflammation control. Genetic polymorphisms in SLC22A4 significantly alter OCTN1 expression, substrate affinity, and drug pharmacokinetics, with strong associations to susceptibility and treatment outcomes in human diseases. Insights from knockout models revealed that OCTN1 deficiency leads to reduced EGT availability, heightened oxidative stress, and aggravated inflammation, particularly in the tissues such as intestine, liver and lung. Moreover, OCTN1 activity is dynamically regulated by epigenetic modifications, cytokines, and hormones, linking it to immune modulation and disease progression. Put together, OCTN1 plays a defined role via high-affinity EGT transport, while its broader transport capacity and pharmacological relevance remain under investigation, with possible - though not yet established - implications for inflammation-associated biomarker development.
Eukaryotic mRNAs typically encode a single functional polypeptide, a principle challenged by the discovery of widespread non-canonical peptide-coding ORFs within 5'UTRs. However, their functional significance at the protein level remains underexplored. Using a four-layered pipeline, we identify 14 human transcripts predominantly transcribed in polycistronic forms, each encoding two conserved proteins. Focusing on the SLC35A4 transcript, we show that its 5'UTR encodes a mitochondrial inner membrane-localized microprotein that we name STREMI (SLC35A4 stress response regulating MICOS interactor). Sharing topology and motifs with the MICOS core subunit MIC10, STREMI regulates mitochondrial cristae morphogenesis in mice and human cells. Additionally, the STREMI-encoding uORF mediates stress-responsive translation of SLC35A4-a Golgi nucleotide sugar transporter-upregulating its translation during the integrated stress response. Evolutionary analyses indicate that these bicistronic transcripts likely arose through transcriptional readthrough following retroposition. We propose a mechanism of "gene symbiosis" that enables functional partitioning and coordinated translation of protein pairs from bicistronic transcripts.
Cytokine-mediated cross-talk between immune cells and fibroblasts is a driver of excessive ECM accumulation during fibrosis. In this study, we used a 3D in vitro model of a connective tissue to discern the roles of three pro-inflammatory cytokines; TNF-α, IL-18 and IL-1β, alone, and in combination with TGF-β1 to simulate the fibrotic environment. Ring-shaped tissues were formed by seeding human fibroblasts into circular molds of agarose, wherein the cells self-assembled, formed a 3D tissue and synthesized de novo a collagen-rich ECM. Cytokine treated tissues were analyzed at days 7 and 14 by histology and measured for thickness, collagen, DNA and strength and stiffness by tensile testing. Despite their pro-inflammatory nature, none of the cytokines increased collagen alone or in combination with TGF-β1. TNF-α and IL-1β reduced collagen, tissue strength and stiffness, and altered tissue morphology. When combined with TGF-β1, TNF-α and IL-1β counteracted TGF-β1-mediated increases in collagen, strength, and stiffness. In contrast, IL-18 had minimal effects alone or when combined with TGF-β1. These data suggest that IL-18 has no effect on fibroblast activation, whereas TNF-α and IL-1β may modulate TGF-β1's effects. This 3D model of a human collagen-rich tissue can help define cytokine-mediated cross-talk between immune cells and fibroblasts.
The progressive skeletal muscle degeneration observed in Duchenne Muscular Dystrophy (DMD) patients requires multiple cycles of satellite cells (SCs) activation to promote tissue regeneration. Dystrophic SCs present intrinsic defects, and the disrupting fibrotic niche hinders appropriate muscle recovery. Traditional 2D culture systems face challenges in modeling the DMD muscle niche and SCs behavior. Our aim was to validate a 3D culture of skeletal muscle spheroids (iSMS) for DMD modeling, as compared to the traditional 2D culture, while investigating the pathophysiological mechanisms of dystrophin deficiency in vitro. To compare iSMS with traditional 2D myogenic differentiation, we differentiated wild-type (WT), dystrophic (DMD) isogenic induced pluripotent stem cells (iPSCs), as well as iPSCs derived from DMD patients, characterized myogenic markers levels and assessed differences in proliferation and differentiation using RT-qPCR, immunofluorescence, and flow cytometry. Our data showed that iSMS improved PAX7 expression in vitro, while MYOD1, MYOG, MYF5, and MYH3 expression were significantly reduced. These findings suggest that, at three weeks of myogenic differentiation, iSMS cultures retained satellite-like cells in a less activated, progenitor-like state. Accordingly, we identified higher expression of canonical Notch signaling genes such as JAG1 and NOTCH1 in iSMS compared to 2D. We also characterized the response of 2D and iSMS to terminal differentiation medium, providing a valuable comparison with muscle fibers derived from human adult myoblasts. Additionally, we showed that DMD iSMS-derived progenitors proliferated at reduced levels compared with WT, a characteristic not observed in progenitors derived from 2D cultures. Finally, we performed iSMS and 2D myogenic differentiation of iPSC lines from three patients with DMD. Our results highlight important advantages of using the iSMS differentiation platform over 2D for DMD in vitro modeling. Exploring these 3D systems may help to gain a deeper understanding of SCs behavior to advance in novel treatments for DMD, which might be applicable to other forms of muscular disorders.
Chronobiology has advanced scientifically since 2000. Translating this knowledge and approach to medicine can alter diagnosis, treatment, and prevention, and improve health. Adding time-of-day (or time-of-year) information is both a concrete and conceptual change to clinical practice and public health relevant to humans and other animals, with low implementation costs. Successful translation of chronobiology to medicine requires new methods, training, and organizational and regulatory action.
Cold preservation is a critical logistical step in liver transplantation but induces ischemia-reperfusion injury (IRI), a key driver of early graft dysfunction. While bulk tissue assays capture global damage, they obscure the cell-type-specific transcriptional programs engaged during hypothermic storage. We utilized a multicellular human liver-on-chip model comprising Patient-Derived Organoids (PDOs), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and macrophages. Chips were exposed to 24-h static cold storage using either the clinical standard University of Wisconsin (UW) solution or a hyperbranched polyglycerol (HPG)-based formulation, followed by normothermic reperfusion. Single-cell RNA sequencing (scRNA-seq) was performed to map transcriptional trajectories across the preservation-reperfusion axis. We identified candidate solution-dependent transcriptional differences across cell types. PDOs from UW-preserved chips showed comparatively higher mean expression of inflammatory and oxidative stress-associated transcripts (IFI27, SAA1, HMOX1) and mitochondrially-encoded genes (MT-ND5) relative to HPG-preserved samples, which retained comparatively higher expression of homeostatic epithelial markers (EPCAM, KRT18). HSCs and LSECs in the UW group showed comparatively elevated expression of fibrosis-associated (COL1A1, TAGLN) and endothelial adhesion (ICAM1) transcripts. Ligand-receptor interaction modelling identified candidate inflammatory communication axes, including chemokine signaling interactions (CXCL1, CCL20) between macrophages and epithelial compartments, with higher predicted activity under UW preservation. This study provides an exploratory, high-resolution map of cell-type-specific transcriptional patterns associated with hypothermic preservation in a liver-on-chip model. Our findings suggest that preservation solution chemistry is associated with distinct transcriptional signatures spanning stress response, mitochondrial, and intercellular signaling pathways. Transcriptional patterns in HPG-preserved cells were consistent with comparatively attenuated injury responses; however, these observations are hypothesis-generating and require independent biological replication and functional validation, including metabolic flux assays and ROS production measurements before conclusions regarding mitochondrial protection or clinical preservation efficacy can be drawn.
The deltoid ligament (DL) is the primary stabilizer of the medial ankle, but its injury mechanisms remain poorly understood. This study aimed to investigate the injury risk and mechanisms of individual DL bundles under both acute and chronic conditions to inform prevention and treatment strategies. A validated finite element model of the human foot was used to examine peak stresses in DL bundles under four acute loading scenarios. Chronic loading was simulated by applying gait loads after transecting the lateral ligaments, and the resulting DL stresses were compared with those of the intact model. Additionally, thirty-nine rats were assigned to three groups: a lateral ligament rupture group (LR, n = 13), a tibialis posterior tendon rupture group (TPR, n = 13), and a sham group (n = 13). After 6 weeks of treadmill running, the mechanical properties and histological characteristics of the DL, along with ankle joint morphology and articular stresses, were evaluated to further verify the hypothesized mechanisms of chronic injury. Under acute loadings, the tibiocalcaneal ligament (TCL), anterior tibiotalar ligament (ATTL), and deep posterior tibiotalar ligament (dPTTL) showed the highest stress under pronation-external rotation loading. Lateral ligament rupture increased DL stress during gait. After 6 weeks of treadmill running, the LR and TPR groups showed roughened articular surfaces with osteophyte formation, increased articular stress, decreased talar bone volume fraction, lower failure load and stiffness ratios of the DL (p < 0.01), reduced fluorescence intensity of COL1, and elevated levels of COL3, MMP-2 and IL-1β compared with the sham group (p < 0.01). The TCL, ATTL, and dPTTL bundles are particularly susceptible to acute injury, with pronation-external rotation posing the greatest risk. Chronic degeneration of the DL occurs following rupture of the lateral ligament or tibialis posterior tendon, with a more pronounced effect after lateral ligament rupture.
The gut microbiome supports digestion, immunity, and metabolism; its imbalance (dysbiosis) drives inflammation and metabolic dysfunction, contributing to chronic diseases such as diabetes, cardiovascular disease, inflammatory bowel disease, and autoimmune disorders. Medicinal plants provide a wide range of phytochemicals (such as polyphenols, flavonoids, alkaloids, saponins), which reach the colon and undergo two-sided interactions with microbes in the gut, acting as potential microbiome modulators and substrates of biotransformation into bioactive metabolites. This structured narrative review synthesises evidence from peer-reviewed studies indexed in PubMed, Scopus, and Web of Science over the last 10 years on the role of medicinal plants in microbiome-mediated chronic disease modulation. This literature is organised into three mechanistic axes: (i) perturbations, defined here as measurable shifts in microbial diversity or taxonomic composition relative to a baseline or healthy reference state, together with beneficial taxa enrichment; (ii) alterations in microbial metabolite output, especially short-chain fatty acids (SCFAs) and other immunometabolic mediators; and (iii) downstream host metabolic and immune signalling. Rather than broad descriptive summaries, the literature is organised using an axis-based mechanistic framework, highlighting key translational constraints such as botanical heterogeneity, dose/formulation variability, and inconsistent microbiome endpoint standardisation, that must be addressed to strengthen human evidence and clinical relevance. Illustrative microbiome-mediated processes involve botanicals such as turmeric (curcumin), ginseng (ginsenosides), and green tea (catechins), though evidence strength varies by study design. Future progress requires standardised phytochemical characterisation, microbiome-stratified trials, and integration of multi-omics with artificial intelligence analytics to enhance mechanistic insight, identify responders, and enable personalised plant-based microbiome therapies.
Propofol is a widely employed intravenous general anesthetic that can induce neurotoxic effects on neurons. Previous research has indicated dysregulation of miR-140-3p in the hippocampal tissues of propofol-treated mice. This research was designed to investigate the function and underlying mechanism of miR-140-3p in propofol-induced neurotoxicity. To simulate propofol-induced neurotoxicity, human SH-SY5Y cells and mice were treated with propofol. Commercial kits were used to measure LDH, MDA, SOD, GSH-Px, and BDNF levels. Cells were transfected with miR-140-3p mimics, inhibitor, or BACE1 overexpression plasmids. Gene expression was assessed by RT-qPCR, cell viability by CCK-8, and apoptosis by flow cytometry. Dual-luciferase and RIP assays confirmed that miR-140-3p targets BACE1. The results confirmed that as the concentration of propofol increased, miR-140-3p levels were progressively downregulated, while BACE1 was correspondingly upregulated. Upregulation of miR-140-3p rescued propofol-treated SH-SY5Y cells from cytotoxicity, as evidenced by enhanced viability, suppressed apoptosis, and ameliorated oxidative stress. Consistently, miR-140-3p overexpression also attenuated propofol-induced neurotoxicity in vivo. Furthermore, BACE1 was confirmed to be a direct target of miR-140-3p through experimental validation, and this post-transcriptional repression was shown to mediate the observed neuroprotection. miR-140-3p attenuates propofol-induced neurotoxicity via BACE1 in vitro and in vivo, providing new insights and a potential biomarker for managing propofol-associated neurotoxicity.
Zoonotic diseases are common threats to global health. A large number of infectious diseases are transmitted from animals to humans. The current study aimed to assess the community's knowledge, attitudes, and practices (KAP) regarding common zoonotic diseases in the Arbaminch district. A cross-sectional survey was carried out between November 2024 and June 2025. A total of 384 participants were interviewed in the study. Participants residing in these areas were randomly chosen. Data were collected using a structured questionnaire. The collected data were analyzed using Stata 17, and the results were reported using descriptive statistics and the chi-square test. The findings of this study revealed that a majority (55%) of participants had good knowledge about zoonotic diseases. Respondents know several modes of transmission for zoonotic diseases, with animal bites (32.5%) being the most recognized, followed by direct contact (15.5%), ingestion of raw products (10%), and inhalation (10%). Regarding attitudes, 63.2% of respondents exhibited a positive attitude towards the importance of zoonotic disease prevention and control, and 67.4% of respondents followed relatively good hygiene and preventive behaviors. However, risky practices were still common. Knowledge score showed a significant association with age. Attitudes of participants were significantly associated with education, age, occupation, and income. Similarly, practices were significantly associated with gender, education level, occupation, and income, with all associations being statistically significant (p < 0.05). The overall community knowledge, attitudes, and practices regarding zoonotic diseases were relatively good.
To develop a semi-automated method to segment "black hole" lesions on post-gadolinium 2D T1-weighted images (GdT1) in multiple sclerosis (MS) that follows radiological intensity rules and perform multi-center validation. Multi-center spin-echo GdT1 images and accompanying proton-density (PD)/T2-weighted images and manual T2 lesion masks of the REFLEXION study (NCT00813709) of suspected/early MS were used. Briefly, the proposed method segments cortical gray matter (GM) to derive a T1-weighted intensity threshold, which is applied inside co-registered T2 lesion masks to segment black hole lesion voxels. It was optimized on a training set (N = 40, 57.5% female, mean age 31.4 ± 8.7 (standard deviation) years), and 274 patients formed the test set (61.3% female, age 31.8 ± 8.4 years). Performance was quantified by the Dice similarity coefficient (DSC) and the intraclass correlation coefficient (ICC) for absolute agreement with manual segmentations. Lesion-wise sensitivity and specificity were calculated. Optimization resulted in: (1) GM selection as minimally 0.8 total WM plus GM partial volume, masked by MNI cortex; (2) normalized mutual information-driven linear co-registration of T2 to GdT1 images, interpolating T2 lesion masks using trilinear interpolation and 0.6 threshold; (3) mean intensity inside GM mask used as upper intensity threshold. The optimized method had acceptable spatial accuracy (DSC: 0.39 ± 0.26) and good volumetric accuracy (ICC: 0.84, 95% CI [0.72, 0.90]. Lesion-wise sensitivity was 0.91 ± 0.19, and lesion-wise specificity was 0.62 ± 0.22. The proposed method to semi-automatically segment black holes from post-gadolinium T1-weighted images shows acceptable performance. As a potential aid to radiologists, the method is not recommended to be used entirely without human intervention. Question T1-hypointense "black hole" lesions reflect disease severity in multiple sclerosis but are not routinely quantified due to a lack of reliable analysis methods. Findings A rule-based semi-automated method for GdT1 "black hole" lesion segmentation was developed and optimized, and then validated in a large unseen multi-center test set. Clinical relevance This method adds quantitative information about GdT1 "black hole" lesions to the radiological assessment of multiple sclerosis disease severity, when false positives are manually removed. This can enhance the characterization of individual patients and advance the understanding of the disease.
Glioblastoma is an aggressive primary brain tumor marked by rapid growth, invasiveness, poor prognosis, and an over 90 % tumor recurrence rate. Current radiation and chemotherapy treatments are limited by non-selectivity and toxicity, creating a need for safer complementary treatments. Historically, natural health products (NHPs) have been used medicinally across cultures for their anti-inflammatory and antioxidant effects. More recently, they have gained recognition for their selective, non-toxic properties in cancer treatment, suggesting their potential as adjuncts to conventional therapies. Black maitake (Grifola frondosa) extract, a well-tolerated NHP with known immunomodulatory properties, has demonstrated anticancer effects in breast cancer models. This study investigates the ability of Black Maitake Odaira Extract - Prothera (BMOE; a trade name of the extract manufactured by Shogun Maitake Canada, London, ON) to induce cell death in the U-87 MG glioblastoma cell line using 2D and 3D models, alone and in combination with the standard chemotherapy: temozolomide (TMZ). Apoptosis was assessed via Hoechst 33,342, annexin V, and propidium iodide staining, along with morphological analyses. Mitochondrial depolarization was measured using TMRM, cell migration was assessed via wound-healing assays, and structural integrity was evaluated using 3D spheroids. BMOE, alone and with TMZ, induced dose-dependent apoptosis, mitochondrial depolarization, and impaired glioblastoma cell migration. BMOE also disrupted 3D spheroid structures and promoted nuclear condensation, consistent with apoptotic processes. Most notably, BMOE significantly enhanced the anti-cancer effects of TMZ. These findings support the potential of BMOE as a complementary therapy that enhances the efficacy of current glioblastoma treatments.
Home environments shape children's dietary habits, but which factors are most influential is unclear. The study purpose was to identify factors in the home environment associated with child intake of fruit and vegetables (FV) and sugar-sweetened beverages (SSBs) using a national dataset collected in 2013-2015 in the U.S. Data from 5,138 school-aged children (4-15 years old) from 130 U.S. communities were collected in 2013-2015. Parents and/or children completed a dietary screener and additional survey questions to assess household socioeconomic status (SES), grocery shopping sources, home food availability, social support for healthy eating, eating out frequency, and other home eating and related behaviors. Other child characteristics included breastfeeding history, intake of school foods, and participation in other nutrition programs. Community variables included predominant race/ethnicity and SES. Classification and regression trees (CART) identified key predictors of intake. The FV and SSB CARTS had 14 and 12 terminal groups, respectively. Children with the highest FV intake (0.54 SD from mean cups/day; 13% of sample) had fruit more often available at home, dark green vegetables more often available at home, ate dinner with family more often, had SSBs less often available at home, and were breastfed longer. Conversely, children in the two groups with the lowest FV intake either had fruit less often available at home, and family never complimented their eating (-0.86; 2%), or they had family that rarely or sometimes complimented their eating, and perceived school lunches as unhealthy (-0.87; 1%). For SSB intake, the lowest consumers (-0.63 SD from mean tsp/day sugar; 17%) never or rarely had SSBs available at home, and lived in higher SES communities. Children in the two groups with the highest SSB intakes had SSBs available at home more often, and lived in a SNAP-participating household and either ate out less often, used a phone/computer for social networking, and had SSBs available at home very often (1.3; 1%), or they ate out more often, and were breastfed for a shorter duration (1.1; 5%). Home availability of FV and SSBs were the most salient predictors of intake of both FV and SSBs, while other predictors differed between FV and SSB intake. Study findings highlight several actionable home-environment strategies to test in future studies to improve school-aged children's diets.
Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. However, the diagnostic sensitivity and specificity of commonly used tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1), remain limited. This study aimed to evaluate the diagnostic value of serum exosomal 3'tiRNA-PheGAA and interleukin-6 (IL-6), alone and in combination with conventional tumor markers, for the detection of NSCLC. Peripheral blood samples were collected from 110 patients with NSCLC and healthy controls. Serum exosomes were isolated, and the expression of 3'tiRNA-PheGAA was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Serum levels of CEA, CYFRA21-1, and IL-6 were determined by electrochemiluminescence immunoassay (ECLIA). The diagnostic performance of individual and combined biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis. Serum levels of 3'tiRNA-PheGAA, IL-6, CEA, and CYFRA21-1 were significantly higher in NSCLC patients than in healthy controls (P < 0.0001). ROC analysis showed that the area under the curve (AUC) values for 3'tiRNA-PheGAA and IL-6 were 0.680 and 0.898, respectively. The combination of 3'tiRNA-PheGAA and IL-6 increased the AUC to 0.926, while the four-marker panel (3'tiRNA-PheGAA, IL-6, CEA, and CYFRA21-1) achieved the highest diagnostic performance with an AUC of 0.971. Serum exosomal 3'tiRNA-PheGAA and IL-6 may serve as promising non-invasive biomarkers for NSCLC diagnosis, and their combination with conventional tumor markers significantly improves diagnostic accuracy.
Residual cardiovascular risk persists despite intensive statin therapy in patients with established atherosclerotic cardiovascular disease (CVD). Omega-3 fatty acids, particularly high-dose eicosapentaenoic acid (EPA), have been proposed as adjunctive therapy, yet trial results conflict, likely due to formulation differences. We conducted a formulation-focused meta-analysis to determine whether high-dose EPA-dominant supplementation reduces cardiovascular events and to quantify the impact of mixed EPA/docosahexaenoic acid (DHA) regimens on efficacy. Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines, we searched MEDLINE, Embase, CENTRAL, and trial registries through May 2025 for randomized controlled trials, including placebo-controlled and open-label designs, of high-dose EPA-dominant omega-3 (≥ 1.8 g/day; ≥ 50% EPA) in adults with established CVD or other high-risk settings. Six trials (n = 42,738; 31-85% male) were eligible. Random-effects models generated pooled risk ratios (RRs), with I2 assessing heterogeneity; sensitivity analyses excluded mixed EPA/DHA formulations. Imaging surrogate outcomes were summarized narratively when study modalities were not directly comparable. EPA-based therapy significantly reduced hospitalizations for unstable angina (RR 0.75, 95% CI 0.66-0.87; I2 = 0%). Overall effects on recurrent myocardial infarction and revascularization were not statistically significant, but both became significant after exclusion of STRENGTH, the only mixed EPA/DHA cardiovascular outcomes trial. No significant effect was observed for ischemic stroke, cardiovascular death, or high-sensitivity C-reactive protein (hs-CRP). CHERRY and EVAPORATE both suggested attenuation of plaque progression, but these imaging studies were not pooled because intravascular ultrasound and coronary computed tomography angiography-derived measures were not directly comparable. High-dose EPA-dominant therapy was associated with fewer unstable angina hospitalizations, and formulation appeared to modify clinical benefit. Among blinded, placebo-controlled, cardiovascular outcomes trials, 4 g/day icosapent ethyl is the only formulation independently associated with reduced cardiovascular events. Larger formulation-specific trials are needed to clarify the roles of purified EPA, mixed EPA/DHA regimens, and patient selection. PROSPERO identifier number: CRD420251063069.
Therapeutic plasma exchange (TPE) is being increasingly utilized in the clinical management of severe rheumatic immune diseases, providing an effective means for rapidly removing pathogenic autoantibodies and inflammatory mediators. However, the non-selective nature of this technique can also lead to the unintended clearance of concomitantly administered antirheumatic drugs, potentially compromising therapeutic efficacy and disease control. Therefore, effective management of potential drug removal process during TPE and the implementation of individualized risk assessment are crucial for optimizing treatment outcomes in patients undergoing TPE. The variability in the extent of drug removal during TPE is primarily determined by their distinct pharmacokinetic characteristics, necessitating the establishment of a systematic, evidence-based strategy for adjusting drug administration regimens in patients receiving TPE treatment. This review synthesizes current evidence from 65 studies on the removal of antirheumatic drugs during TPE, identifying key determinants influencing clearance rates, including volume of distribution, protein binding, molecular size, and elimination half-life. Our analysis reveals that the risk of drug removal exists as a continuous spectrum: large monoclonal antibodies (e.g., rituximab, natalizumab), characterized by a large molecule size, low volume of distribution, with which mostly confined to the vascular space, are cleared with high efficiency. This finding supports the clinical recommendation of administering such drugs after TPE. For drugs with limited direct evidence, we propose a predictive model based on fundamental pharmacokinetic parameters to estimate their removal risk and guide clinical decision-making. Based on this evidence, we have constructed a stratified clinical management framework. It aims to maintain effective therapeutic drug exposure levels during chronic TPE therapy and to provide a rationale for the judicious application of TPE in overdose scenarios. Implementing this pharmacokinetic-informed, risk-adapted individualized strategy is important for ensuring treatment continuity, enhancing patient safety, and advancing empiricism-based therapy towards precision medicine.
Acetabular fractures are uncommon, but serious injuries. Demographic changes may have a significant impact on planning healthcare structures to improve treatment outcomes. Aim of this nationwide, registry-based retrospective controlled study was to identify incidence trends, demographic characteristics, and care structures of patients with acetabular fractures in Germany. We analyzed inpatient data from the Institute for the Hospital Remuneration System (InEK). Based on 52 095 patients with primary diagnosis of an acetabular fracture between 2019 and 2024, we calculated incidence rates for different age-groups and put a spotlight on geriatric acetabular fractures (> 65 years of age). Incidence rates in patients under 65 years remained stable, whereas patients over 65 years showed a significant age-dependent increase with an exponential rise in men aged 80 + with the highest incidence being 122.4/100 000 inhabitants annually. We recorded high levels of co-morbidity and nursing care dependency for elderly patients after acetabular fracture. Although 43% of patients were treated in hospitals > 500 beds, acetabular fractures were managed across all hospital sizes. There is a rapidly increasing incidence of geriatric acetabular fractures, predominantly driven by elderly male patients over 80 years. Patients over 65 years are associated with high rates of co-morbidities and nursing care levels.